Synthesis of new carboxylate ligands for simulation of binuclear active centers of nonheme oxygenases

Full text of DOI:10.1023/A:1016523912095

Russian Journal of Organic Chemistry, Vol. 38, No. 4, 2002, pp. 606 608. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 4, 2002,
pp. 634 636.
Original Russian Text Copyright
2002 by Gumanov, Shteinman, Nordlander, Koldobskii.
SHORT
COMMUNICATIONS
Synthesis of New Carboxylate Ligands for Simulation
of Binuclear Active Centers of Nonheme Oxygenases*
L. L. Gumanov1, A. A. Shteinman1, E. Nordlander2, and G. I. Koldobskii3
1Institute of Problems of Chemical Physics, Russian Academy of Sciences,
Chernogolovka, Moscow oblast, 142432 Russia
2Ebbe Nordlander, Inorganic Chemistry 1, Chemical Center, Lund University, Sweden
3St. Petersburg State Technological Institute, St.Petersburg, Russia
Received November 1, 2001
In binuclear active centers of nonheme iron-con-
taining enzymes activating molecular oxygen:
methanemonooxygenase (MMO), ribonucleotide-
permits the synthesis of binuclear iron(II) complexes
with low coordination number, affords complexes of
higher solubility in nonpolar solvents, and provides a
possibility of modelling the hydrophobic surrounding
of the binuclear center.
reductase (RNR),
-decaturase, toluenemonooxy-
genase etc the coordination surrounding of iron is
characterized by the presence of four carboxylate
donors (from Asp and Glu). Therewith one or two
among these carboxylates form bridges between iron
atoms, and the remaining together with two imid-
azoles (from His) complete the coordination sphere
of each iron atom as terminal ligands [1].
Taking into account that the models with the
sterically hindered benzoates are promising it seems
advantageous to increase the range of these ligands
using ortho-substituents of various size, form, and
conformational mobility and to develop new synthetic
routes to such structures.
Two approaches were suggested for increasing the
kinetic stability of carboxylate complexes. One
approach consists in application of a polydentate
ligand whereas the kinetic stability increases due to
chelate effect [2, 3].
Thus the problem consists in the synthesis of new
carboxylate ligands with bulky substituents of various
size and flexibility. It is presumable that skilful com-
bination of sterical effects from nitrogen and carboxy-
late donors should provide a possibility of varying
iron complex structures in order to attain the structure
of model complexes which would best reproduce the
structure and dynamics of the active center.
It was shown recently [4, 5] that the use in the
model systems of sterically hindered benzoates
enhanced the kinetic stability of the carboxylate
ligand by its shielding with bulky ortho-substituents
of the benzoate. At the same time this approach
We report here on the synthesis of new carboxylate
ligands for simulation of binuclear active centers of
*
The study was carried out under financial support of CRDF (grant 2058) and INTAS (grant 97-1289).
1070-4280/01/3804-606$27.00 2002 MAIK Nauka/Interperiodica

SYNTHESIS OF NEW CARBOXYLATE LIGANDS
607
The lithium 2,6-diphenoxybenzoate was obtained
by passing a flow of dry carbon dioxide through a
solution of lithium derivatives of 1,3-diphenoxybenz-
ene. A free acid III was obtained by controlled
acidification of the salt. Its pure lithium salt was
prepared for complexation study by boiling of the
acid in toluene with lithium hydride.
on UV spectra the complex was assigned a structure
of binuclear -oxocomplex of trivalent iron.
The lithium salt of ligand III and salt V with
Fe(OTf)2(MeCN)2 in a mixture acetonitrile toluene
gave rise to pale straw-colored complexes of Fe(II)
that by analogy to complex of ligand II prepared
under the same conditions [5] was assigned a struc-
ture of binuclear complexes Fe2(OCOR)4(MeCN)2.
The final conclusions on the structure of Fe(II)
complexes with ligands I V should be based on the
X-ray diffraction analysis whose results will be
published elsewhere.
2,6-Bis(2-methoxycarbonylphenoxymethyl)pyri-
dine (I). A mixture of 8.5 g (79 mmol) of 2,6-luti-
dine, 32.5 g (182 mmol) of N-bromosuccinimide, and
0.15 g of azobisisobutyronitrile in 300 ml of benzene
was stirred at 50 C for 24 h at irradiation with a lamp
of ethched glass of 200 W power. Then the reaction
mixture was treated with 10% solution of Na2CO3
(2 100 ml), washed with water (100 ml), benzene
was removed under reduced pressure, and the residue
was extracted with hexane (2 50 ml). On distilling
off hexane under reduced pressure we isolated 6.7 g
(32%) of 2,6-bis(bromomethyl)pyridine as a yellowish
crystalline substance that was used further without
additional purification. The repeated bromination
with smaller charge resulted in 15% yield.
We failed to prepare ligand IV by direct tritylation
of resorcylic acid with trityl chloride under conditions
applied to tritylation of phenols. The ditrityl deriv-
ative thus obtained was used in the synthesis of
2,6-ditrityloxybenzoic acid by the procedure of ligand
III preparation (yield 23% with respect to
resorcinol). However the best results were obtained
at direct tritylation of the resorcylic acid under
conditions of the phase-transfer catalysis formerly
developed for tritylation of five-membered nitrogen-
containing heterocycles [7]. At the treating of the
resorcylic acid with trityl chloride in a system
dichloromethane aqueous NaOH in the presence of
Bu4NBr the corresponding ditrityl derivative was
obtained in 56% yield.
To a solution of 3.0 g (11.3 mmol) of 2,6-bis-
(bromomethyl)pyridine in 25 ml of anhydrous acetone
was added a solution of 3.5 g (23 mmol) of methyl
salicylate in 25 ml of acetone, 1.5 g of anhydrous
potassium carbonate, and 50 mg of dibenzo-18-
crown-6. The mixture was stirred at 45 50 C for
15 h. On completion of the reaction acetone was
evaporated at reduced pressure, the residue was
treated with benzene (100 ml), filtered, and on
evaporating the benzene at reduced pressure we
obtained 3.26 g (71%) of crude 2,6-bis(2-methoxy-
carbonylphenoxymethyl)pyridine (I). The pure com-
pound was obtained as colorless crystals after two
1
recrystallizations from acetone. mp 120 C. H NMR
spectrum (CDCl3), , ppm: 7.91 d (2H, -H-P-),
7.83 t (1H, -H-P-), 7.74 d (2H, C6H4, p-), 7.45
7.51 m (C6H4, °-), 7.01 7.06 m (4H, C6H4, m-),
5.03 s (4H, OCH2N), 3.96 ©(6H, OCH3). Found, %:
C 67.76; H 5.35; N 3.45. C23H21NO6. Calculated, %:
C 67.80; H 5.20; N 3.44.
We carried out preliminary investigation of new
ligands complexing with Fe(II) under argon atmo-
sphere. A reaction of sodium salt of ligand II with
Fe(ClO4)2 10H2O in methanol furnished a yellow
complex that turned green at oxidation in air. Basing
2,6-Bis(2-carboxyphenoxymethyl)pyridine (II).
Reagent I (1 g) was boiled for 15 h in 50 ml of 2%
water solution of NaOH, then the mixture was cooled,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 4 2002

608
GUMANOV et al.
neutralized with 5% HCl till pH 6, the separated
colorless precipitate was filtered off and dried in air
(0.91g, 97%). After recrystallization from 2-propanol
we obtained 0.7 g of compound II as colorless
was evaporated at reduced pressure, the solid residue
was washed with ether and dried in a high vacuum.
After recrystallization from benzene we obtained
7.15 g (56%) of acid IV, mp 224 226 C (decomp).
1
1
crystals, mp 210 C. H NMR spectrum (CD3CN), ,
IR spectrum, , cm : 750, 850, 1038, 1078, 1244,
1
ppm: 8.16 d (2H, -H-Py), 7.85 t (1H, -H-Py),
7.55 t (2H, C6H4, o-), 7.44 d (2H, C6H4, p-), 7.11
7.16 m (4H, C6H4, m-), 5.48 s (4H, OCH2N). Found,
%: C 66.42; H 4.74; N 3.64. C21H17NO6. Cal-
culated, %: C 66.48; H 4.52; N 3.69.
1391, 1444, 1487, 1594. H NMR spectrum (CDCl3),
, ppm: 7.29 s (1H, C6H3, p-), 7.05 (2H, C6H3),
6.96 7.03 m (20H, tr). Found, %: C 84.43; H 5.54.
C45H34O4. Calculated, %: C 84.62; H 5.37.
IR spectra were recorded on spectrometer UR-20
from KBr pellets, NMR spectra were registered on
spectrometers Varian-300 and Tesla at operating
frequencies 300 and 100 MHz respectively.
2,6-Diphenoxybenzoic acid (III). To a solution
of 22 g (0.08 mol) of 1,3-diphenoxybenzene and
15 ml (0.105 mol) of tetramethylethylenediamine in
200 ml of anhydrous hexane at 10 C was added drop-
wise under argon atmosphere a solution of 0.12 mol
of butyllithium in 150 ml of hexane. In 3 min after
completion of butyllithium addition the reaction mix-
ture became turbid, and a separation of granular
colorless precipitate gradually started. The stirring
was continued for 1 h at 10 15 C, then at cooling
through the reaction mixture a flow of dry carbon di-
oxide (35l, 1.5 mol) was passed. After that the stir-
ring was continued for 1 h more, and at vigorous
stirring was added 400 ml of water. The water layer
was separated and thrice washed with 200 ml of
hexane, then it was acidified till pH 5, the separated
precipitate was filtered off and dried in a vacuum
desiccator over P2O5. Yield 19 g (77%), mp67 68 C.
1H NMR spectrum (CDCl3), , ppm: 7.29t (4H, Ph,
m-), 7.13t (1H, C6H3), 7.05t (6H, Ph, o-+ p-), 6.55 d
(2H, C6H3). Found, %: C 74.35; H4.78. C19H14O4.
Calculated, %: C 74.50; H 4.61.
Reagents from Aldrich and Iancaster Companies
were
used
without
additional
purification.
Fe(OTf)2(MeCN)2 was obtained by procedure [8].
The authors are grateful to P. S. Mozhaev for the
help in syntheses.
REFERENCES
1. Wallar, V.J. and Lipscomb, J.D., Chem. Rev., 1996,
vol. 96, no. 6, pp. 2625 2658.
2. Berchet, L., Collomb-Dunand-Sauthier, M.-N., Du-
bourdeaux, P., Moneta, W., Deronzier, A., and
Latour, J.-M., Inorg. Chim. Acta, 1998, vol. 282,
no. 1, pp. 243 246.
3. Trukhan, V.M., Gritsenko, O.N., Nordlander, E., and
Shteinman, A.A., J. Inorg. Biochem., 2000, vol. 79,
pp. 41 46.
4. Lee, D. and Lippard, S.J., J. Am. Chem. Soc.,
1998, vol. 120, no. 46, pp. 12153 12154.
5. Hagadorn, J.R., Que, L., Jr., and Tolman, W.B., J. Am.
Chem. Soc., 1998, vol. 120, no. 51, pp. 13531 13532.
6. Trukhan, V.M., Nordlander, E., and Shteinman, A.A.,
Zh. Org. Khim., 1999, vol. 35, no. 2, pp. 334 336.
7. Artamonova, T.V., Nordlander, E., and Koldob-
skii, G.I., Zh. Org. Khim., 2000, vol. 36, no. 5,
pp. 767 770.
2,6-Bis(trityloxy)benzoic acid (IV). To a mixture
of 3.08 g (0.02 mol) of resorcylic acid, 0.5 g of tetra-
butylammonium bromide, 50 ml 20% NaOH, and
15 ml of dichloromethane under argon atmosphere
was gradually added at slight stirring 12.27 g
(0.044 mol) of trityl chloride in 35 ml of dichloro-
methane. The mixture was stirred for 3 h, the organic
layer was separated, washed with water, dried with
anhydrous potassium carbonate, the dichloromethane
8. Hagen, K.S., Inorg. Chem., 2000, vol. 39, no. 25,
pp. 5867 5869.
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